U.S. patent number 4,722,941 [Application Number 05/911,165] was granted by the patent office on 1988-02-02 for readily absorbable pharmaceutical compositions of per se poorly absorbable pharmacologically active agents and preparation thereof.
This patent grant is currently assigned to Kali-Chemie Pharma GmbH. Invention is credited to Theodor Eckert, Reinhard Hempel, Fritz H. Kemper, Martin Wischniewski.
United States Patent |
4,722,941 |
Eckert , et al. |
February 2, 1988 |
Readily absorbable pharmaceutical compositions of per se poorly
absorbable pharmacologically active agents and preparation
thereof
Abstract
A readily absorbable pharmaceutical composition of
pharmacologically active agents, which per se are poorly
absorbable, is disclosed which comprises a pharmacologically
effective amount of at least one such pharmacologically active
agent distributed in a vehicle comprising an absorption-enhancing
amount of at least one fatty acid of medium chain length. The
preparation is suited for formulating pharmacologically active
bases, cardiac glycosides, steroids, antibiotics,
sympathicomimetica, tranquilizing agents, or local
anaesthetics.
Inventors: |
Eckert; Theodor (Muenster,
DE), Kemper; Fritz H. (Muenster, DE),
Wischniewski; Martin (Neustadt a. Rbge., DE), Hempel;
Reinhard (Hanover, DE) |
Assignee: |
Kali-Chemie Pharma GmbH
(Hanover, DE)
|
Family
ID: |
4306435 |
Appl.
No.: |
05/911,165 |
Filed: |
May 31, 1978 |
Current U.S.
Class: |
514/784; 514/221;
514/262.1; 514/420; 514/534; 514/535; 514/653; 514/786;
514/946 |
Current CPC
Class: |
A61K
9/4858 (20130101); A61K 47/14 (20130101); A61K
47/12 (20130101); Y10S 514/946 (20130101) |
Current International
Class: |
A61K
47/14 (20060101); A61K 47/12 (20060101); A61K
031/40 (); A61K 031/195 (); A61K 031/415 (); A61K
047/00 () |
Field of
Search: |
;424/180,244,258,265,365 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
2357389 |
|
Nov 1973 |
|
DE |
|
1432784 |
|
Apr 1976 |
|
GB |
|
Primary Examiner: Griffin; Ronald W.
Attorney, Agent or Firm: Schwartz, Jeffery, Schwaab, Mack,
Blumenthal & Evans
Claims
What is claimed is:
1. A method of enhancing the absorption of an enterally or
topically administered pharmacological active agent capable of
eliciting a physiological effect in a human or animal subject, said
active agent comprising a basic compound selected from the group
consisting of antibiotics, antispasmodic agents, agents which are
effective in improving coronary disorders, anti-inflammatory
agents, sympathicomimetically active agents, tranquilizers and
local anaesthetics, which method comprises the step of concurrently
administering to the subject an amount of said active agent
effective to produce the desired physiological effect and a vehicle
comprising an absorption enhancing amount of a free fatty acid of
medium chain length containing from about 6 to about 12 carbon
atoms.
2. The method as defined in claim 1, wherein the per se poorly
absorbable pharmacologically active basic agent is selected from
the group consisting of valethamatebromide, bencyclane,
dipyridamole, indomethacine, synephrine, diazepam,
7-chlor-1-methyl-2-(hydroxymethyl)-5-(2'-chlorophenyl)-1H-2,3-dihydro-1,4-
benzodiazepine and procaine.
3. The method as defined in claim 1, wherein the amount of fatty
acids of medium chain length is between about 1 and about 100%
weight of the vehicle.
4. The method as defined in claim 3, wherein the total amount of
fatty acids of medium chain length is from about 20 to about 100%
by weight of the vehicle.
5. The method as defined in claim 1, wherein the pharmacologically
active basic agent is administered in the form of an acid addition
salt with a pharmaceutically acceptable acid.
6. The method as defined in claim 5, wherein the acid is a fatty
acid containing from about 6 to about 18 carbon atoms.
7. The method as defined in claim 5, wherein the acid is a fatty
acid containing from about 6 to about 12 carbon atoms.
8. The method as defined in claim 1, wherein the amount of the
fatty acid of medium chain length in the vehicle is substantialy
the amount which is necessary to form an acid addition salt of the
pharmacologically active basic agent and wherein the vehicle
further comprises at least one glyceride selected from the group of
mono- and diglycerides of fatty acids containing from about 6 to
about 18 carbon atoms and mixtures thereof.
9. The method as defined in claim 1, wherein said administering
step comprises enteral administration.
10. The method as defined in claim 1, wherein said administering
step comprises topical administration.
11. The method as defined in claim 1, wherein said vehicle further
comprises at least one free fatty acid containing from about 12 to
about 18 carbon atoms.
12. The method as defined in claim 1, wherein said vehicle further
comprises at least one glyceride selected from the group consisting
of tri-, di-, and monoglycerides or mixtures thereof
13. The methods as defined in claim 12, wherein the glyceride is a
fatty acid glyceride.
14. The methods as defined in claim 13, wherein the glyceride is
selected from the group consisting of mono- and diglycerides of
fatty acids and mixtures thereof.
15. The method as defined in claim 13, wherein the fatty acid
within the glyceride comprises from about 6 to about 18 carbon
atoms.
16. The method as defined in claim 13, wherein at least part of the
fatty acids within the glycerides are saturated fatty acids.
17. The method as defined in claim 13, wherein at least part of the
fatty acids within the glycerides are unsaturated fatty acids.
18. The method as defined in claim 13, wherein the fatty acids are
selected from the group consisting of capric acid, caprylic acid,
palmitic acid, stearic acid, and oleic acid.
19. The method as defined by claim 1, wherein said active agent
comprises diazepam.
20. The method as defined by claim 1, wherein said active agent
comprises
7-chlor-1-methyl-2-(hydroxymethyl)-5-(2'-chlorophenyl)-1H-2,3-dihydro-1,4-
benzodiazepine.
21. The method as defined by claim 1, wherein said active agent
comprises an aliphatic or heterocyclic amine group.
Description
BACKGROUND OF THE INVENTION
The present invention relates to readily absorbable pharmaceutical
formulations of pharmacologically active agents, in particular
bases, which are poorly absorbable per se, and to a method for
preparing such formulations.
It is well known in the art that in order to obtain a similar
pharmacological effect, a number of pharmacologically active agents
require considerably higher dosages if administered in oral,
rectal, or percutaneous dosage form than if administered
parenterally by means of injection. This is an indication that such
pharmacologically active agents are absorbed only to a low extent
from these formulations.
Yet, there is a need for pharmaceutical formulations which provide
such per se poorly absorbable pharmacologically active agents not
only in an injectable formulation, but also in orally and/or
rectally and/or percutaneously applyable formulations which provide
a high degree of enteral absorption of these pharmacologically
active agents.
Various methods for improving the absorbability of such
insufficiently absorbable pharmacologically active ingredients are
known in the art. In some cases the absorbability can be improved
by means of a technological treatment of the pharmacologically
active agent, e.g., by means of micronization, complex-formation,
or addition of solubility improving additives. Yet, these
techniques exhibit a number of disadvantages.
Special apparatuses or additional process steps during the
preparation and/or formulation process are required for some of
these methods; or only a limited number and amount of additives can
be applied in certain cases due to safety and/or compatability
problems. Furthermore, these techniques can successfully be applied
only to a limited number of groups of pharmacologically active
agents.
Recently, glycerides of fatty acids of medium chain length,
containing from about 6 to about 12 carbon atoms, have been used as
carrier materials for pharmacologically active ingredients. Yet
only a very limited group of pharmacologically active agents can be
satisfactorily formulated using triglycerides a a carrier material,
due to a poor solubility of most pharmacologically active
ingredients in such a carrier material. In particular, various
difficulties are encountered, if pharmacologically active bases are
to be formulated with glycerides, since these compounds are not
sufficiently stable in free base form, and in salt form are not
sufficiently soluble.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide enteral and
topical pharmaceutical formulations of pharmacologically active
agents which per se are poorly absorbable, which provide for a high
degree of enteral or percutaneous absorption of such
pharmacologically active agents.
It is a further object of the present invention to provide such an
enteral formulation wherein the enteral absorption of the per se
poorly absorbable pharmacologically active agents is increased
sufficiently to permit an enteral application of these
pharmacologically active agents.
It is a special object of the present invention to provide such a
formulation of per se poorly absorbable pharmacologically active
bases, in particular aliphatic and/or heterocyclic amines.
It is a further special object of the present invention to provide
such a formulation of per se poorly absorbable cardiac glycosides,
in particular of g-strophanthin, k-strophanthin, or proscillaridin,
preferably such a formulation wherein the enteral absorption of
poorly absorbable glycosides is sufficiently high to insure a
constant degree of absorption of such glycosides after enteral
application.
It is a further special object of the present invention to provide
such a formulation of per se poorly absorbably steroids, e.g.,
steroid hormones and derivatives thereof, in particular
pregn-4-ene-3,20-diones and pregna-4,6-diene-3,20-diones, such as
progesterone, medrogestone and similar gestagenes.
It is a further special object of the present invention to provide
such a formulation of per se poorly absorbable antibiotics, such as
griseofulvin.
It is a further special object of the present invention to provide
such a formulation of per se poorly absorbable tranquilizers, e.g.,
benzodiazepine derivatives.
It is a further object of the present invention to provide such a
formulation of per se poorly absorbable sympathicomimetica, such as
(hydroxphenyl)-ethanolamine derivatives or indol derivatives.
It is a further object of the present invention to provide such a
formulation of per se poorly absorbable local anaesthetics such as
procaine.
It is a further object of the present invention to provide such a
formulation of per se poorly absorbable antispasmodics, e.g.,
antispasmodically active dialkylaminoethanol derivatives, for
example, bencyclane or valethamate-bromide.
It is a further special object of the present invention to provide
such a formulation of per se poorly absorbably antiinflammatory
agents such as indomethacine.
It is a further object of the present invention to provide such a
formulation of per se poorly absorbable coronary therapeutic, in
particular, coronary vasodilators, such as dipyridamole.
It is a further object of the present invention to provide topical
pharmaceutical formulations of pharmacologically active agents
which ensure a ready penetration from the site of application into
the skin, preferably into the deeper layers thereof, and/or a
permeation through the skin and absorption into the body
system.
It is a further object of the present invention to provide such a
topical formulation of primarily locally effective
pharmacologically active agents, such as antiinflammatory agents,
analgesics, local anaesthetics, and antirheumatics, which provide
for an increased speed and degree of permeation.
It is a further object of the present invention to provide such a
topical formulation of primarily systemically-effective
pharmacologically active agents (which upon enteral application are
largely normally destroyed in the gastric-intestinal tract and/or
in the liver) which provide for a sufficiently high speed and
degree of permeation and absorption of these systemically-effective
agents through the skin to permit a cutaneous application
thereof.
In order to accomplish the foregoing objects and advantages of the
present invention, there is provided a readily absorbable
pharmaceutical composition which comprises a pharmacologically
effective amount of at least one per se poorly absorbable
pharmacologically active agent distributed in a vehicle comprising
an absorption enhancing amount of at least one fatty acid of medium
chain length.
The preparation according to the present invention is preferably
suited for formulating per se poorly enterally and/or
percutaneously absorbable pharmacologically active bases, e.g.,
pharmacologically active compounds including a basic mono-, di-,or
trisubstituted aliphatic or heterocyclic amino group in their
molecule.
Preferably, the vehicle further comprises at least one glyceride of
a fatty acid of medium or long chain length.
According to the present invention, there is further provided a
process for preparing a readily absorbable pharmaceutical
composition of a per se poorly absorbable pharmacologically active
agent which comprises the step of dissolving the agent in a vehicle
comprising at least one fatty acid of medium chain length.
According to the present invention, there is further provided a
method of enteral or percutaneous medication which comprises
enterally, preferably orally, or percutaneously administering the
above described pharmaceutical composition to a larger mammal.
DETAILED DESCRIPTION OF THE INVENTION AND ITS PREFERRED
EMBODIMENTS
It has been found that fatty acids of medium chain length exhibit
an unexpectedly high dissolution capacity for many
pharmacologically active agents, in particular, pharmacologically
active bases, and that surprisingly not only the solubility but
also the enteral and/or percutaneous absorbability of these agents
is highly increased in the presence of fatty acids of medium chain
length. By dissolving the pharmagologically active agent in a
vehicle containing fatty acids of medium chain length, its
lipophilic properties are increased and its absorption, e.g.,
through the intestinal mucosa, is increased. The beneficiary effect
of the resulting improved absorption is further increased by the
fact that, contrary to fatty acids of long chain length, fatty
acids of medium chain length are transported into the major
circular system directly through the portal vein instead of passing
through the lymphatic system. Thus, the pharmacologically active
agents also can reach their site of action more rapidly and under
less loss.
Fatty acids of medium chain length comprise fatty acids, preferably
saturated monocarboxylic acids, having a chain length of preferably
between about 6 and about 12, most preferably between about 8 and
about 10 carbon atoms, and mixtures thereof. Especially suited are
capric and caprylic acid and mixtures thereof. Of course, these
fatty acids may be used either singly or in form of mixtures
thereof, wherein the ratio between the various acids can take any
desired value.
The compositions according to the present invention may further
comprise fatty acids having a chain length of from about 12 to
about 18 carbon atoms. The addition of such fatty acids of long
chain length may be advisable in some cases in order to obtain a
desirable consistency and/or melting range of the composition.
According to a preferred embodiment of the invention, the
composition further comprises glycerides of fatty acids in addition
to the pharmacologically active agent and the fatty acid of medium
chain length. In this manner, the good dissolution capacity of the
fatty acids of medium chain length can be further increased for
some of the pharmacological agents, in particular if partial
glycerides of fatty acids of medium or long chain length are
used.
Partial glycerides of fatty acids of medium and long chain length
comprise mono- and diglycerides of saturated and/or unsaturated
fatty acids, having a chain length of between about 6 and about 18
carbon atoms, and mixtures thereof. Especially suited are mono- and
diglycerides of capric, caprylic, oleic, palmitic, and stearic
acids and mixtures thereof. There are no limitations as to what the
ratio between various glycerides in glyceride mixtures may be. The
proportions of glycerides in the composition therefore may be
choosen to best suit the desired properties of the composition
depending on the type and consistency of the formulation and its
intended mode of application, the type and amount of the
pharmacologically active agents, and the type and amount of fatty
acids of medium chain length which are present in the composition,
and commercial availability of the respective glycerides or fatty
acids.
The term "pharmacologically active agent" as used in the present
specification and claims is meant to denote agents which are
effective in larger mammals, in particular human beings, in
treating or preventing diseases and/or disorders in the body
functions and/or influencing the state of the body and its function
in a desirable manner.
The term "per se poorly absorbable" as used in the present
specification and claims is meant to denote such agents, which upon
being enterally or cutaneously applied in a solid or liquid
formulation devoid of any dissolution and/or absorbability
improving additives exhibit such a low and/or slow per se
absorability, that by means of enteral or topical administration, a
pharmacologically effective level in the body of larger mammals
cannot be reached or can be reached only by administering a dosage
which corresponds to at least 2 times the parenterally effective
dosage of the respective agent, or that in the case of enteral
application only less than 50% of the enteral dosage which is
necessary to achieve a pharmacologically effective level of the
respective agent in the body are actually absorbed in the
gastro-intestinal tract.
Whether the actual per se absorbability of a respective
pharmacologically active agent is sufficient or insufficient, of
course, will depend on the chemical and physical properties of said
agent, especially the kind and degree of its pharmacological
activity as well as the desired pharmacological effect.
Enteral formulations according to the present invention are suited
for enteral application of pharmacologically active agents which
per se ar poorly absorbable from the gastro-intestinal tract.
Topical formulations according to the present invention ar suited
for cutaneous application of such pharmacologically active agents
which exhibit a primarily local activity in the body near the site
of their application, yet which per se exhibit an unsatisfactorily
slow and/or poor penetration into and/or permeation through the
skin. Topical compositions according to the present invention are
also suited for applying such pharmacologically active agents which
possess a primarily systemic activity, yet which upon oral
administration exhibit undesirable side effects in the
gastro-intestinal tract and/or which are at least partially
destroyed in the gastro-intestinal tract.
Poorly absorbable pharmacologically active agents, which are
advantageously applied in form of a formulation according to the
present invention, include pharmacologically active bases, in
particular amines, cardiac glycosides, steroids, antibiotics,
spasmolytica, agents which are effective in improving coronary
disorders, anti-inflammatory agents, sympathicomimetica,
tranquilizers, and local anaestetics.
The term "cardiac glycosides", as it is used in the present
application, includes cardiotonically active glycosides containing
a cardenolidor bufadienolid aglycon, which is substituted in the
3-position by a glycosidic group containing 1 to 4 sugar units, and
semi-synthetical derivatives thereof. The sugar units may be
pentose or hexose units or partial reduction products thereof.
Cardiotonically active semi-synthetic derivatives of
naturally-occuring cardiac glycosides include the aglycones
themselves, glycosides wherein the original number of sugar units
is reduced, glycosides wherein the glycosidic group and/or the
aglycon are chemically modified by etherification or esterification
of at least part of the hydroxy groups with lower alkyl or lower
carboxylic acyl, hydroxylation or dehydrogenation.
Among the cardiac glycosides with cardenolid structure, there may
be cited the digitalis glycosides which occur naturally in
digitalis purpurea and digitalis lanata and derivatives thereof,
e.g., lanatosids A, B, or C, purpurea glycosides A or B, digitoxin,
digoxin or gitoxin or the aglycons thereof, k-strophanthus
glycosides which occur naturally in strophanthus kombe,
g-strophanthus glycosides which occur naturally in strophanthus
gratus, e.g., k-strophanthins .alpha.,.beta., and .gamma.
containing the aglycon k-strophanthidin (=3.beta.,
5,14-trihydroxy-19-oxo-5.beta.-card-20(22)-enolid) and
g-strophanthin containing the aglycon g-strophanthidin
(=1.beta.,3.beta.,5,11.alpha.,14,19-hexahydro-5.beta.-card-20(22)-enolid).
Among the cardiac glycosides with bufadienolid structures, there
may be cited the squill glycosides which occur naturally in scilla
martima, e.g., proscillaridin, scillaren A, scillaren B.
Preparations according to the present invention are especially
suited for the enteral application of such cardiac glycosides which
per se are particularly poorly enterally absorbable, for example,
cardiac glycosides of which only about 5% or less, e.g., between
about 5 and 0.3% are enterally absorbed. Examples of per se poorly
enterally absorbable cardiac glycosides are g-strophanthin,
k-strophanthin and proscillaridin.
The concentration of the cardiac glycoside in the enteral
preparations according to the present invention may vary
considerably depending on the physical and chemical properties,
especially the pharmacological activity of the respective cardiac
glycoside which is used, on its enteral absorbability per se, and
on its sensitivity to metabolic decompositions in the
gastro-intestinal tract and/or the liver, as well as on the amount
of absorption enhancing fatty acids of medium chain length and
partial glycerides present in the preparation and the contemplated
mode of administration, the treated condition and the therapy which
is desired. Usually, a satisfactory enteral activity is obtained
with an amount corresponding to between about 1 and about 3 times,
preferably about 1 and about 2 times the parenterally-effective
amount of the respective cardiac glycosides. For example,
enterally-effective amounts of g-strophanthin, k-strophanthin or
proscillaridin within the compositions according to the present
invention are between about 0.1 and about 0.3, preferably about 0.2
and 0.25 mg per single dosage unit.
Preparations according to the present invention are also suited for
the application of steroids which per se are particularly poorly
absorbable.
The term "steroids" as it is applied in the present application
includes steroid hormones, in particular gestagene hormones, and
synthetic and semi-synthetic derivatives thereof, especially
pregn-4-ene-3,20-diones and pregna-4,6-diene-3,20-diones. Examples
of per se poorly enterally absorbable steroids are progesterone and
medrogestone.
The pharmacological properties of the steroids and the medical
application thereof are well known in the art.
The concentration of the steroid in preparations according to the
present invention may vary considerably depending on the physical
and chemical properties, especially the pharmacological activity of
the respective steroid which is used, and on its absorbability per
se, as well as on the amount of absorption enhancing fatty acids of
medium chain length and partial glycerides present in the
preparation and the contemplated mode of administration, the
treated condition and the pharmacological effect which is desired.
Usually a satisfactory enteral activity is obtained with an amount
corresponding to between about 1 and about 3 times, preferably
about 1 and about 2 times the parenterally effective amount of the
respective steroid. For example, enterally-effective amounts of
progesterone or medrogestone within the compositions according to
the present invention are between about 2 and about 50 mg per
single dosage unit.
Preparations according to the present invention are also suited for
the application of antibiotics which are per se poorly absorbable,
for example, griseofulvin.
The concentration of griseofulvin preparations according to the
present invention may vary considerably depending on the amount of
absorption enhancing fatty acids of medium chain length and partial
glycerides present in the preparation and the contemplated mode of
administration, the treated condition and the pharmacological
effect which is desired. Usually a satisfactory antibiotic activity
is obtained in enteral and topical compositions containing between
about 50 and about 150 mg of griseofulvine per single dosage
unit.
Preparations aocording to the present invention are also suited for
the application of sympathicomimetically active agents which are
per se poorly absorbable, for example, phenylalkanolamine
derivatives such as N-(lower alkyl)phenyl-ethanolamines and
propanolamines wherein the phenyl may be substituted by 1 or 2
hydroxy groups, e.g., synephrine.
The concentration of the sympathicomimetic agent in the
preparations according to the present invention may vary
considerably depending on the physical and chemical properties,
especially the pharmacological activity of the respective agent
which is used, and on its absorability per se, as well as on the
amount of absorption enhancing fatty acids of medium chain length
and partial glycerides present in the preparation and the
contemplated mode of administration, the treated condition and the
pharmacological effect which is desired. For example, in the case
of enteral formulation of synephrine, the amount per single dosage
unit preferably is between about 20 and about 60 mg.
Preparations according to the present invention are also suited for
the application of tranquilizers, especially benzodiazepine
derivatives, such as diazepam or
7-chloro-1-methyl-2-(hydroxymethyl)-5-(2'-chlorophenyl)-1H-2,3-dihydro-14-
benzodiazepine. The amount of these tranquilizing benzodiazepine
derivatives in enteral compositions according to the present
invention suitably is between about 5 and about 25 mg per single
dosage unit.
Preparations according to the present invention are also suited for
the application of antispasmodically active agents, for example,
antispasmodically active di-loweralkylaminoethyl ester and ether
derivatives, e.g., valethamate-bromide or bencyclane.
The concentration of the spasmolytically active agents in the
preparations according to the present invention may vary
considerably depending on the physical and chemical properties,
especially the pharmacological activity of the respective agent
which is used, and on its absorbability per se, as well as on the
amount of absorption enhancing fatty acids of medium chain length
and partial glycerides present in the preparation and the
contemplated mode of administration, the treated condition and the
pharmacological effect which is desired. Enteral preparations of
bencyclane for example may comprise an amount of from about 25 to
about 100 mg per single dosage unit.
Preparations according to the present invention are also suitable
for the application of agents which are effective in preventing
and/or ameliorating coronary disorders or insufficiencies, for
example, coronary vasodilators such as dipyridamole.
Preparations according to the present invention are also suitable
for the applications of anti-inflammatory agents such as
indomethacine or local anaesthetics such as procaine.
Basic pharmacologically active agents may be incorporated into the
compositions according to the present invention in free base form
or in form of a salt with a pharmaceutically acceptable acid,
preferably a fatty acid containing from about 6 to about 18,
preferably from about 6 to about 12 carbon atoms.
According to a preferred embodiment of the present invention, the
composition comprises a pharmacologically effective amount of a
pharmacologically active base, only such an amount of a fatty acid
of medium chain length which essentially is sufficient to form an
acid addition salt of the basic pharmacologically active agent and
at least one glyceride, preferably a partial glyceride.
The amount of absorption enhancing fatty acids of medium chain
length in the preparations according to the present invention,
which is effective to sufficiently enhance the enteral or
percutaneous absorption to permit an enteral or cutaneous
administration of the per se poorly absorbable pharmacologically
active agent may vary considerably depending on the per se
absorbability of the respective agent, as well as on the chemical
and physical properties of any other ingredients of the
composition, in particular on its content in partial glycerides.
Typically, satisfactory results are obtained with preparations
wherein the total amount of fatty acids of medium chain length and
of partial glycerides is between about 20 and about 100%,
preferably about 40 and about 100% of the vehicle.
The enteral formulations according to the present invention, may
take the form of solid or liquid formulations for oral or rectal
application. Thus, the formulations may be in the form of capsules,
tablets, coated tablets, suppositories, or emulsions.
The topical formulations according to the present invention may
take the form of compositions having a semisolid consistency, such
as ointments, creams, jellies, foams, aerosols, or the like, or the
form of liquid solutions, suspensions, and emulsions, preferably in
non-aqueous solvents.
Depending on the type of the pharmacological agent therein, the
desired consistency and the contemplated mode of application, the
carrier material in the vehicle composition according to the
present composition may essentially consist of only the fatty acids
of medium chain length or of mixtures of these acids with partial
glycerides of fatty acids of medium and long chain length or may
comprise additional carrier materials. These formulations can
easily be prepared according to the present invention, since the
partial glycerides which are utilized according to the present
invention comprise partial glycerides which at room temperature are
liquid as well as such partial glycerides which at room temperature
are solid. By mixing the appropriate partial glycerides, nearly any
desired consistency can be obtained and/or a melting point which is
suitable for rectally applied suppositories can be achieved.
If desired, enteral formulations may further comprise conventional
pharmaceutical carriers and additives, for example,
viscosity-improving and/or structure- or matrix-forming additives
which provide for an appropriate viscosity and physical structure.
Suitable such additives are, e.g., inorganic or organic thickening
and structure-forming agents such as saturated higher fatty acids
and alcohols containing, e.g., 12 to 20 carbon atoms, for example,
stearic or palmitic acid, stearic or cetylic alcohol, waxes like
beeswax, synthetic esters of higher fatty acids and higher fatty
alcohols, or partial glycerides of fatty polyhydroxy acids (e.g.,
the commercial product "Softigen 701"). Suppositories may further
contain any conventional water soluble or fatty suppository bases
as additional vehicles. The compositions may further comprise
pharmaceutical adjuvants, e.g., binders or lubricants for
tabletting, stabilizing-, flavoring-, or emulsifying agents or
preservatives.
If the pharmacologically active ingredients within the enteral
composition are sensitive to strong acids, it may be advisable to
apply an enteric coating to the oral dosage forms, e.g., gelatin
capsules, of such agents.
Topical formulations according to the present invention may further
comprise additional carriers, such as pharmacologically-acceptable
oils and wax, and/or such supplementary pharmaceutical adjuvants
which are conventionally used in topical formulations, e.g., in
conventional bases for ointments, creams, and jellies. In many
cases it may be advisable to incorporate a structure-forming,
thickening or gel-forming agent into the composition. Suitable such
agents are, in particular, highly dispersed silicic acid (e.g., the
commercial product "Aerosil"), bentonites, modified
montmorillonites, such as alkyl ammonium salts of montmorillonites
(e.g., the commercial products "Bentone"), wherein the alkylgroups
may contain 1 to 20 carbon atoms, e.g., dimethyl-dialkyl-ammonium
salts wherein the alkylgroups contain 16 to 18 carbon atoms,
organic structure-forming, thickening and suspending agents, e.g.,
cetostearylic alcohol and modified castor oil products (e.g., the
commercial product "Antisettle CVP".RTM.)). Creams may be in the
form of emulsions, which may contain conventional
pharmaceutically-acceptable emulsifying agents.
The formulations according to the present invention are prepared in
any conventional manner, e.g., by dissolving the per se poorly
absorbably pharmacologically active agents in the fatty acids of
medium chain length, optionally adding additional adjuvants, and
formulating the resulting mixture into the desired dosage form by
known pharmaceutical methods, e.g., tabletting, molding into
suppositories, or filling into capsules.
If a basic pharmacologically active agent is formulated together
with a salt-forming amount of the fatty acid of medium chain length
and glycerides, it is not necessary to separately prepare a salt of
the base and the fatty acid and subsequently dissolve this salt in
the glycerides. Yet, according to a preferred embodiment of the
process, the free base is dissolved in a mixture of the fatty acid
and the glycerides, preferably partial glycerides. In this case the
free fatty acid in the mixtures serves to form an acid addition
salt with the pharmacologically active base.
The high enteral absorption of the formulations according to the
present invention is demonstrated by determination of the level of
the respective pharmacological agents in the blood and
determination of the amount of the pharmacologically active agent
which is excreted through the kidneys.
The level of
7-chloro-1-methyl-2-(hydroxymethyl)-5-)2'-chlorophenyl)-1H-2,3-dihydro-14-
benzodiazepine (which in the following will be abbreviated as
"tranquilizer KC 1956") in the blood after oral application has
been determined in humans.
The blood level values of tranquilizer KC 1956 which indicate the
degree of its bioavailability from the applied compositions have
been determined after oral application of the tranquilizer in form
of a conventional composition and in form of a composition
according to the present invention.
The following compositions are used:
______________________________________ (a) Capsules A: containing
KC 1956 in a conventional formulation
______________________________________ KC 1956 micronized 10
mg/capsule Lactose (D 80) 121 mg/capsule Corn starch 57 mg/capsule
Gelatin 2 mg/capsule Primojel.sup.+ 8 mg/capsule Magnesium stearate
2 mg/capsule Total 200 mg/capsule
______________________________________ (b) Capsules B: containing
KC 1956 in a composition according to the present invention
______________________________________ KC 1956 10.0 mg/capsule
Capric acid 29.0 mg/capsule Imvitor 742 .RTM..sup.++ 261.0
mg/capsule Total 300.0 mg/capsule
______________________________________ .sup.+ carboxymethylstarch
(Manufacturer Verenigde Zetmeelbedrijven "De Bijenkorf" N.V.)
.sup.++ highly purified mixture of mono and diglycerides of oleic
acid comprising about 40% of monoglyceride and about 60% of
diglyceride (Manufacturer Dynamit Nobel AG.).
Capsules A contain the tranquilizer KC 1956 in micronized form,
that is the form that is the best absorbable form acording to the
present state of the art. Capsules B contain the tranquilizer KC
1956 in a composition according to the present invention,
comprising an amount of fatty acid of medium chain length which is
sufficient to form fatty acid addition salts of KC 1956 and a
mixture of partial glycerides.
10 mg of the tranquilizer in form of the above described
compositions is administered orally to test persons on an empty
stomach, followed by ml of water. Blood samples are taken at
1/2-hour intervals during the first 3 hours after application and
at 5 and 7 hours after application. The amount of KC 1956 in the
blood samples is determined by means of gas-chromatography. The
results are given in Table I below. In Table I the average blood
level values of groups of 6 test persons each for three different
modes of application, are given in nanogramm/ml plasma as a
function of the time at which the blood samples have been
taken.
TABLE I ______________________________________ BLOOD LEVEL OF KC
1956 IN HUMANS IN ng/ml PLASMA AFTER ORAL APPLICATION OF 10 mg OF
KC 1956 (N = 6) KC 1956 CAPSULES A KC 1956 CAPSULES B TIME -x
s.sup.-.sub.x -x s.sup.-.sub.x
______________________________________ 30 Min. 10.9 1.8 24 6.9 1 h
10.5 1.7 34 4.0 1.5 h 6.4 0.9 24 4.6 2 h 4.2 0.3 17 5.1 2.5 h 3.3
0.3 -- -- 3 h 2.6 0.2 12 3.1 5 h 2.4 1.1 5 0.7 7 h 1.9 1.9 4 0.7
______________________________________
As can be seen from the data in Table I, by means of the
formulation according to the present invention (capsule B), the
systemic availability of the tranqualizer as well as its maximum
blood level are increased to about three times the values which are
obtained by means of the conventional composition (capsules A).
The renal excretion of procaine after oral application of procaine
contained in a formulation according to the present invention is
determined in 3 female test persons in the following cross-test
procedure.
The total amount of aromatic diazotizable amino groups in the
amount of urine which is collected within 72 hours is determined
and serves as a measure of the rate of excretion of procaine.
Firstly, a blank-value from a urine collected within 24 hours is
determined for the test persons. Then 25 mg of procaine
hydrochloride are administered orally and the total amount of
excreted diazotizable aromatic amino groups in the urine collected
within 72 hours is determined. The results obtained after
subtraction of the blank-value indicate an absorption rate of
50-60% of the administered amount of procaine-hydrochloride.
In the same manner as described above the resorption rate of
procaine is determined after oral application of the following
procaine-containing compositions according to the present
invention:
______________________________________ 21.7 mg Procaine-base
(corresponding to 25 mg of procaine hydrochloride) 40 mg Capric
acid 40 mg Lauric acid 100 mg Mono-diglyceride mixture of fatty
acids of medium chain length (C.sub.6 -C.sub.12) 201.7 mg Total
______________________________________
The results of this test indicate a total absorption rate of
between 80 and 90% of the procaine from this composition, that is
an average increase of 54%.
The determination of the amount of diazotizable aromatic
amino-groups is carried out as follows:
The total amount which has been excreted within 72 hours is
calculated by adding the amounts which are determined in each of
the total amounts of urine which are collected in each of the three
twenty-four hour periods. 2 ml samples of the urine, which is
collected within 24 hours, are added to 3 ml of 1N-NaOH and are
heated on a water-bath for a period of 20 minutes. Subsequently, 4
ml of 1N-HCl are added and the mixture is cooled and filled up with
water to an amount of 10 ml. 1 ml of a 0.1% sodium nitrite solution
are added to 4 ml of the above mixture. The resulting mixture is
allowed to stand for a period of 3 minutes, then 1 ml of a 0.5%
amidosulfuric acid solution is added, the mixture is thoroughly
shaken and again allowed to stand for a period of 3 minutes. Then,
2 ml of a 0.1% solution of N-(naphthyl)-(1))-ethylene-diammonium
dichloride is added and subsequently the resulting mixture is
filled up with water to an amount of 10 ml. This diluted solution
is allowed to stand for 10 minutes and then the extinction at 545
nm is determined. From the results, the total amount of
diazotizable amino groups within the total amount of urine
collected within 24 hours is calculated and the resulting values
are added to obtain the total amount which has been excreted within
the 72 hour period.
The invention will now be further illustrated by means of the
following examples.
Unless stated otherwise, the term "parts" is meant to denote parts
by weight.
EXAMPLE 1
10 g of g-strophanthin are dissolved in 20 kg of a mixture
comprising 70 parts of lauric acid and 30 parts of capric acid
under heating to a temperature of 40.degree. C. 500 mg portions
(corresponding to 0.25 mg of g-strophanthin) of the resulting
mixture are filled into gelatin capsules at a temperature which is
above the solidification temperature of the mixture of 36.degree.
C. The capsules are allowed to solidify and subsequently are
provided with an enteric coating in a conventional manner.
EXAMPLE 2
10 g of g-strophanthin are dissolved in 10 kg of a mixture of
capric acid and mono-glyceride of oleic acid under heating to a
temperature of 40.degree. C. Portions of 250 mg of the resulting
mixture (corresponding to 0.25 mg of g-strophanthin) are filled
into gelatin capsules at a temperature which is above the
solidifying temperature of the mixture of 37.degree. C.
EXAMPLE 3
250 g of medrogestone are dissolved in 2.5 kg of a mixture
comprising 40 parts of capric acid and 60 parts of lauric acid
under heating to a temperature of 40.degree. C. Portions of 250 mg
of the resulting mixture (corresponding to 25 mg of medrogestone)
are filled into gelatin capsules at a temperature above the
solidifying temperature of the mixture which is 30.degree. C.
EXAMPLE 4
500 g of griseofulvin in micronized form are dissolved or else
suspended in 5 kg of a mixture comprising equal parts of capric
acid and lauric acid under heating to a temperature of 40.degree.
C. The resulting mixture which solidifies at a temperature of
30.degree. C., is micro-encapsulated by means of spray-drying in a
conventional manner. The resulting dry powder can be formulated
into solid dry dosage forms, such as tablets, pellets, or
granulates.
EXAMPLE 5
500 g of griseofulvin in micronized form are dissolved or else
suspended in 5 kg of a mixture containing equal parts of capric
acid and lauric acid under heating to a temperature of 40.degree.
C. The resulting mixture is mixed with 2.5 kg of diglyceride of
capric acid, 2 kg of eucerinum anhydricum .RTM. (mixture of wool
alcohols in highly purified aliphatic hydrocarbons, Manufacturer
Beiersdorf AG) and 0.5 kg of beeswax to obtain an ointment.
EXAMPLE 6
200 g of synephrine-base are dissolved in 800 g of a mixture of
capric and lauric acid under heating to a temperature of 40.degree.
C. Portions of 250 mg of the resulting mixture (corresponding to 50
mg of synephrine-base) are filled into gelatin capsules at a
temperature which is above the solidifying temperature of the
mixture of 30.degree. C.
EXAMPLE 7
165 g of synephrine-base and 290 g of caprylic acid are dissolved
in 500 g of a mixture of mono- and diglycerides of fatty acids of
medium chain length (C.sub.8-C.sub.10), namely the commercial
product "Witafrol 7420.RTM.*. Portions of 239 mg of the resulting
mixture (corresponding to 41.25 mg of synephrine-base) are filled
into gelatin capsules.
EXAMPLE 8
217 g of procaine-base, 400 g of capric acid, and 400 g of lauric
acid are dissolved in 1000 g of a mixture of mono- and diglycerides
of fatty acids of medium chain length, namely the commercial
product Witafrol 7420.RTM.*. Portions of 202 mg of the resulting
mixture (corresponding to 21.7 mg of procaine-base) are filled into
gelatin capsules.
EXAMPLE 9
714 g of bencyclane-base, 650 g of capric acid, and 650 g of lauric
acid are dissolved in 1000 g of a mixture of mono- and diglycerides
of fatty acids of medium chain length, namely the commercial
product Witafrol 7420.RTM.*. Portions of 211 mg of the resulting
mixture (corresponding to 50.0 mg of benzyclane-base) are filled
into gelatin capsules.
EXAMPLE 10
714 g of benzyclane-base, 650 g of capric acid and 650 g of lauric
acid are dissolved in 4000 g of a mixture of mono- and diglycerides
of fatty acids of medium chain length, namely the commercial
product Witafrol 7420.RTM.*. The resulting solution is incorporated
into 13.986 kg of a molten suppository mixture (commercial product
Witepsol H 5.RTM.**) under agitation, and the resulting mixture is
molded into suppositories of 2000 mg each (corresponding to 71.4 mg
of bencyclane-base).
EXAMPLE 11
100 g of diazepam and 290 g of capric acid are dissolved in 2.61 kg
of a mixture of mono- and diglycerides of fatty acids of medium
chain length (commercial product Imvitor 742.RTM.***) at a
temperature of 35.degree. C. Portions of 300 mg of the resulting
mixture (corresponding to 10 mg of diazepam) are filled into
gelatin capsules.
EXAMPLE 12
100 g of
7-chloro-1-methyl-2-(hydroxymethyl)-5-(2'-chlorophenyl)-1H-2,3-dihydro-14-
benzodiazepine (tranquilizer KC 1956) and 290 g of capric acid are
dissolved in 2.61 kg of a mixture of mono- and diglycerides of
fatty acids of medium chain length (commercial product Imvitor
742.RTM.***) at a temperature of 35.degree. C. Portions of 300 mg
of this mixture (corresponding to 10 mg of the tranquilizer KC
1956) are filled into gelatin capsules.
* * * * *